抑郁症日益频发是精神卫生领域的重要挑战。前期实验我们发现NMDA受体内源性配体D-丝氨酸在抑郁症模型鼠伏隔核等脑区含量显著降低。我们研究已证实前额叶皮层-伏隔核神经环路中NMDA受体功能下调并发突触可塑性损害在抑郁症中发挥重要作用，但具体机制尚不明确。鉴此，我们推测：伏隔核区D-丝氨酸下调可能是抑郁症NMDA受体功能减退及行为障碍发生的重要原因，上调伏隔核区D-丝氨酸将通过增强NMDA受体功能改善抑郁模型的突触功能及行为表现。本项目拟建立慢性社会挫败及慢性轻度不可预见应激模型，采用行为学、神经电生理和分子生物学、慢病毒载体基因干预等技术，研究①抑郁发生过程中伏隔核区D-丝氨酸及相关代谢合成酶的变化；②D-丝氨酸水平下降在模型鼠NMDA受体功能下调中的作用；③伏隔核内局部调节D-丝氨酸水平对动物抑郁样行为的影响。本研究有助于揭示D-丝氨酸信号在抑郁症发病中的作用，为该病的防治提供新认识。

Major depression is a common, recurrent and serious mental illness that affects millions of people worldwide. Our preliminary experiments have found that there were significant decreases in D-serine content in nucleus accumbens and prefrontal cortex in major depression animal model. Our team has identified NMDA receptors in the prefrontal cortex-nucleus accumbens circuit as a key regulator in the modulation of persistent psychomotor plasticity in major depression animal model. However, the mechanisms underlying this effect of NMDA receptors have not been investigated. Therefore, we proposed that decreased brain D-serine might contribute to the hypofunction of NMDARs and the onset of behavioral disorders in depression, and regulating brain D-serine would improve the behavioral performances via enhancing NMDARs function. Chronic social defeat stress and chronic unpredictable mild stress models will be used to evaluate the relation between D-serine in the nucleus accumbens and major depression. Based on these evidences, we are going to use various methods, including behavioral, electrophysiological, biochemical and molecular biological techniques and lentiviral-gene interference to explore: 1) endogenous D-serine concentration and amount and activity of the key enzymes in the NAc extract in the pathogenesis of major depression; 2) D-serine regulates the function and expression of NMDA receptors in the NAc of major depression animals; 3) D-serine in the NAc regulates behavioral performance in animal models of depression. We hope to reveal the role of endogenous D-serine in the pathogenesis of major depression, providing new information for the pathophysiology of depression and proposing a new strategy for the treatment of depression.